Circulating tumor DNA (ctDNA) dynamics and survival outcomes in patients (pts) with advanced non-small cell lung cancer (aNSCLC) and high (&gt;50%) programmed cell death-ligand 1 (PD-L1) expression, randomized to cemiplimab (cemi) vs chemotherapy (chemo).
Authors: Natalie I Vokes, David R. Gandara, Ahmet Sezer, Saadettin Kilickap, Mahmut Gumus, Igor Bondarenko, Mustafa Özgüroğlu, Miranda Gogishvili, Haci M. Turk, Irfan Cicin, Dmitry Bentsion, Jinrui Liu, Nicholas Giangreco, Fang Wang, Siyu Li, Israel Lowy, Jean-Francois Pouliot, Giuseppe Gullo, Petra Rietschel, Vladimir Jankovic
Journal: Journal of Clinical Oncology (2023)

9022 Background: While ctDNA has emerged as a promising tool for monitoring response on therapy, there is a paucity of data from prospective, randomised Phase 3 studies to establish clear criteria for the clinical application of ctDNA. In the EMPOWER-Lung 1 study, first line (1L) cemi monotherapy improved overall survival (OS) vs platinum chemo in pts with aNSCLC, PD-L1 ≥50%, and no EGFR, ALK, or ROS1 aberrations and an acceptable risk/benefit profile. We performed personalized tumor-specific analysis of ctDNA from pts treated in the EMPOWER-Lung 1 study to determine the optimal time point and magnitude of ctDNA variation that are associated with OS and progression-free survival (PFS). Methods: Tumor tissue next-generation sequencing was performed to identify tumor-specific DNA variants. ctDNA levels were monitored using personalized pt specific probe sets (Natera, Foundation Medicine) in the plasma at baseline, end of week 3 (W3) and W9. Endpoints included overall response rate (ORR) complete or partial response (CR/PR), stable disease (SD) and progressive disease (PD) per RECIST 1.1, OS and PFS. Association between ctDNA decrease and clinical endpoints was tested in 3 groups of pts defined by sensitivity analysis: no-decrease, any decrease (molecular response, MR), and complete clearance (complete MR, cMR) of ctDNA. Results: ctDNA analysis was performed on samples from 175 pts (chemo n = 89; cemi n = 86). Baseline characteristics, ORR, OS, and PFS were comparable to those of the intention to treat population. At W9, cMR/MR was associated with clinical response to cemi (CR/PR: 97%, SD:58%, PD:17%), but not with clinical response to chemo, as it was detected in the majority of chemo pts across all RECIST categories (CR/PR: 100%, SD:90%, PD:80%). In the cemi arm, ctDNA cMR was associated with the longest survival, with median OS (mOS) not-reached compared to pts with MR (mOS of 29 months) and pts with no-decrease (mOS of 8 months), as well as statistically significant hazard ratios (cMR vs MR: W9 HR = 8, 95% CI 1.8-35, p = 0.0056; cMR vs no-decrease: W9 HR = 25, 5.7–110, p = 0.000021 and W3 HR = 5.9, 1.4-25, p = 0.017). Delayed MR/cMR (i.e., MR/cMR at W9 but not at W3) was observed in 8/66 pts (12%), and transient MR (i.e., MR at W3 but not W9) in 9/66 pts (14%), with available ctDNA data at both timepoints. Conclusions: This is the largest data set to date correlating ctDNA levels with efficacy outcomes from a randomized clinical trial comparing chemo with immunotherapy in 1L aNSCLC. The results indicate that lack of treatment-induced decrease in ctDNA may identify pts with inferior OS benefit from cemi monotherapy as early as 3 weeks following initiation of therapy and can inform future use of early ctDNA response assessment in prospective interventional studies. Clinical trial information: NCT03088540 .